The narcotic antagonists (-)-naloxone (Narcan) and (-)-naltrexone (Trexan) are life-saving antidotes that rapidly reverse narcotic overdose. Their (+)-enantiomers (mirror image forms) have no effect on narcotic overdose and were long thought to be pharmacologically inert compounds. We first prepared and characterized unnatural (+)-naloxone in 1978 as an opioid receptor inert research tool useful for detecting opioid receptor mediated effects when used in conjunction with (-)-naloxone. In recent years, we have shown that (+)-naloxone and (+)-naltrexone are functional antagonists of toll-like receptor 4 (TLR4) and that selective functional antagonism of TLR4 by (+)-naloxone can result in reversal of neuropathic pain as well as potentiation of opioid analgesia. TLR4 is known to be involved in many physiological functions via mediation of glial activation including, neuropathic pain, compromised acute opioid analgesia, and unwanted opioid side effects (tolerance, dependence, and reward) and inflammation. Attenuation of glial activation has been shown to both to alleviate exaggerated pain states induced by experimental pain models and to reduce the development of opioid tolerance. TLR4 activation and platelet activation factor elevation are components of the inflammatory process that launches the process resulting in birth. We studied the issue of premature delivery in the mouse and found that (+)-naloxone suppressed preterm delivery induced by the TLR4 agonist lipopolysaccharide (LPS) in late gestation. It also suppressed preterm birth and perinatal death induced by sterile heat killed E. coli following intrauterine administration. Overall our results confirm that platelet activation factor induction of preterm delivery is mediated by and dependent on TLR4, and indicate that the small molecule TLR4 antagonist (+)-naltrexone is a potent inhibitor of PAF-induced preterm birth and fetal inflammatory injury. We plan to further investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting.